This invention relates to new, fast acting pharmaceutical formulations comprising short acting hypnotic agents that are useful in the short-term treatment of insomnia, such as transient insomnia.
Insomnia is a common disorder characterized by difficulty in the initiation and/or maintenance of sleep. Insomnia periodically affects 30% of adults. Furthermore, more than 90% of the total population have trouble with sleep at some point during their lives.
Inadequate sleep impairs quality of life and ability to function normally in a general sense. It often results in adverse personal, medical or psychiatric consequences, in addition to increasing the risk of accidents.
The disorder can be transient or chronic. Although isolated incidents of short-term insomnia may be caused by, for example, grief, stress, or short-term exposure to substances that are known to impair sleep, many patients who suffer from transient insomnia may experience the disorder regularly and/or periodically on a short-term basis.
In the treatment of short-term insomnia, consideration needs to be given to the potential side effects of the medicament employed, including any associated drug dependency. The practitioner also needs to be aware of the potential for undesirable absorption of drug taking place several hours after administration, which may give rise to decreased alertness and impaired psychomotor function during normal activity the following day. In this respect, wherever possible, it is important to expose patients only to short-term, or “on-demand”, use of the lowest effective dose of any particular drug.
Zolpidem (N,N-dimethyl-2-(6-methyl-2-p-tolylimidazo-[1,2-a]pyridin-3-yl)acet-amide) is a short-acting sedative that is used in the short-term management of insomnia. The drug possesses a short half-life and produces no active metabolites. It appears to act by binding to the benzodiazepine receptor component of the GABA receptor complex and accordingly possesses similar properties to the benzodiazepines. However, zolpidem has the general advantage of minimal anxiolytic, myorelaxant and convulsant properties.
Currently-available zolpidem formulations comprise doses of between 5 and 10 mg of the drug in the form of its hemitartrate salt (see, for example, British National Formulary, Volume 48, pages 174 and 175). These compositions are administered orally, typically before retiring, and rapidly disintegrate in the gastrointestinal tract to provide for systemic absorption of drug.
Although zolpidem is rapidly absorbed from the gastrointestinal tract, its bioavailability is reported to be 70% following oral administration. Peak plasma concentrations are thereby typically reached within 1 and 5 hours of oral administration using current formulations.
In view of this, onset of action can be delayed in many patients, leading to a frustrating lack of “on demand” sleep, in addition, in many cases, to undesirable residual effects (such as those mentioned hereinbefore) the following day. Equally importantly, in view of the first-pass and/or pre-systemic metabolism that is typically connected with oral administration, the use of currently-marketed zolpidem formulations is characterised by considerable inter- and intra-individual variability in terms of both onset of action and residual effects (see, for example, Holm et al, Drugs (2000) 59, 865; Darcourt et al, J. Pharmacol., (1999) 13, 81; Terzano et al, Drug Safety (2003) 26, 261; Salva and Costa, Clin. Pharmacokinet. (1995) 29, 142: Drover et al, Clin. Ther. (2000) 22, 1443; and “Guidance for Industry; Labelling Guidance for Zolpidem Tablets”, US Department of Health and Human Service (1997)).
Thus, there is a clear unmet clinical need for an improved formulation comprising a short acting hypnotic agent, such as zolpidem, which exhibits, in a consistent fashion, a more rapid, and preferably almost instantaneous, onset of action (e.g. within minutes rather than hours), as well as fewer residual effects the following day.
A biphasic peroral dosage form comprising zolpidem has recently been described in inter alia U.S. Pat. No. 6,514,531 B1. This system provides for an initial immediate release phase to induce sleep as rapidly as is possible with existing commercial formulations. This is followed by a controlled-release phase with the objective of maintaining sleep following induction. Other biphasic tablets comprising zolpidem are disclosed in European patent application EP 1 260 216 A1.
U.S. Pat. No. 6,638,535 B2 also discloses sustained release pellets comprising short acting hypnotic agents, such as zolpidem, zopiclone and zaleplon which provides for an in vitro release of less than 60% of active ingredient within the first 5 minutes of the in vitro test.
International patent application WO 00/16750 discloses a drug delivery system for the treatment of acute disorders by mucosal administration, in which the active ingredient is in microparticulate form and is adhered to the surface of larger carrier particles in the presence of a bioadhesion and/or mucoadhesion promoting agent.
International patent application WO 03/059349 discloses oral dosage forms comprising inter alia zolpidem, in addition to a solubility enhancer (e.g. a surfactant) and a spheronization agent (e.g. a distilled monoglyceride).
The skilled person would expect that transmucosal administration of an active ingredient across the pulmonary, nasal or oral mucosa (e.g. sublingual administration) would give rise to an enhanced rate of absorption of that active into plasma (as compared to an oral formulation), and thereby result in a vastly increased bioavailability at an early stage following administration. In the treatment of insomnia with a short acting hypnotic agent such as zolpidem, such an enhanced rate of absorption might be expected to give rise to potential safety problems in patients that are sensitive to the drug, potentially giving rise to undesirable pharmacological effects, such as a more rapid onset of sleep than is convenient (e.g. when preparing for sleep; see, for example col. 2, lines 9 to 18 of U.S. Pat. No. 6,638,535 B2). Moreover, the skilled person would also expect such a rapid absorption to compromise the duration of action of the relevant drug, and thereby the ability to maintain sleep during the night, especially given that short acting compounds are known to rapidly eliminated from plasma (see, for example, col. 2, lines 19 to 31 of U.S. Pat. No. 6,638,535 B2).
Surprisingly, we have found that safe and reliable “on demand” sleep induction (and maintenance) may be provided by way of a formulation as described hereinafter.